Previous studies have investigated the cellular inflammatory response and regulation of inflammatory cytokines following spinal cord injury (SCI). Infiltration of inflammatory cells and corresponding cytokine production has been predicted to contribute to secondary injury via several mechanisms, and studies suggest that inhibition of inflammation can be beneficial to recovery. Conversely, other studies have raised the tantalizing possibility that, at least under some conditions, stimulation of the cellular immune system may provide neuroprotective benefits or enhance recovery from CNS injury. Critically, however, the principal humoral immune component of these inflammatory events, the complement cascade, has not been investigated. While antibodies are a critical component of homologous (host) defense, complement is a principal effector of both the innate and adaptive immune system. Our preliminary data provide novel evidence for: 1) complement immunoreactivity in association with neurons, oligodendrocytes, and axons after SCI, 2) improved functional recovery and histological outcome following complement depletion in contusion-injured rats, and 3) improved functional recovery in mice deficient in the C5 component of complement. In this proposal, we investigate the mechanism of action of complement depletion in SCI, cellular source of complement after SCI, and predominant pathway(s) for complement-mediated impairments in functional recovery and tissue damage after SCI. We hypothesize that: 1) The functional improvements derived from complement depletion will be associated with inhibition of neutrophil, macrophage/monocyte, microgial, and T-cell recruitment, inhibition of neuron and oligodendrocyte cell loss, and reduction in glial scar formation; 2) In addition to serum-derived complement from Blood-Spinal Barrier (BSB) opening immediately after injury, local CNS cell synthesis is a component of complement deposition after SCI; and 3) Complement-mediated impairments in functional recovery and tissue damage activation after SCI are predominantly dependent upon the terminal pathway. These studies will provide an understanding of the specific pathological role of complement activation after SCI, and clarify appropriate potential targets for therapeutic complement inhibition in SCI, which will be increasingly important as new complement inhibitors are brought to clinical trials for CNS injury.